Quaternary derivatives of noroxymorphone which relieve nausea and emesis

ABSTRACT

Quaternary derivatives of noroxymorphone are used to prevent or relieve nausea and emesis associated with the use of narcotic analgesics without interfering with the analgesic activity of the drugs. A particularly preferred compound is methylnaltrexone. The compound is administered in a concentration between 0.25 mg/kg and 1.0 mg/kg prior to or concurrently with the administration of the narcotic analgesic.

BACKGROUND

The administration of therapeutic doses of morphine and other clinicallyuseful narcotic analgesics is often accompanied by unpleasant sideeffects on the gastro-intestinal system. For instance, morphine andrelated opiates such as meperidine and methadone may retard intestinalmobility by causing contractions of the small bowel circular smoothmuscle.

Morphine and related narcotics may also induce nausea and increasedmobility of the gastro-intestinal tract resulting in emesis or vomiting.These side effects are caused by direct stimulation of the chemoreceptortrigger zone for emesis in the area postrema of the medulla. (Goodmanand Gilman, The Pharmacological Basis of Therapeutics, page 502 [6th ed.1980], incorporated herein by reference.) Studies have shown thatmorphine and other narcotics cause emesis in dogs. For example, Wang andGlaviano, JPET 111: 329-334 (1943), incorporated herein by reference,reported that administration of 0.5 mg/kg of morphine intravenously to12 dogs resulted in emesis in 9 dogs within an average of 2.4 minutes.(Mg/kg refers to milligrams of morphine per kilograms of body weight.)When 1.0 mg/kg of morphine was administered intramuscularly to 13 dogs,12 of them vomited within an average time of 3.5 minutes.

SUMMARY OF THE INVENTION

U.S. Pat. No. 4,176,186 to myself and others disclosed treatment ofintestinal immobility associated with the use of narcotic analgesicsthrough the administration of quaternary derivatives of noroxymorphone.It has now been discovered that the same compounds are also useful forthe treatment, both prophylactic and therapeutic, of the nausea andvomiting associated with the administration of these drugs.

According to the invention, therefore, nausea and vomiting bywarm-blooded animals receiving morphine and related opiates, meperidine,methadone or the like, may be prevented or relieved by theadministration of methylnaltrexone or other quaternary derivatives ofnoroxymorphone represented by the formula: ##STR1## wherein R is allylor a related radical such as chloroallyl, cyclopropyl-methyl orpropargyl, and

X is the anion of an acid, especially a chloride, bromide, iodide ormethylsulfate anion.

These compounds are administered to the animal either prior to orsimultaneously with the administration of the narcotic analgesic. Theymay be administered either enterally or parenterally. There has not beenobserved any interference with the analgesic activity of the opiates.

As used herein, unless the sense of the usage indicates otherwise, theterm "morphine" refers to any narcotic analgesic.

DETAILED DESCRIPTION

This invention relates to the use of quaternary derivatives ofnoroxymorphone to prevent or relieve nausea and vomiting associated withthe administration of morphine to warm-blooded animals. The usefulcompounds are represented by the formula: ##STR2## wherein R is allyl ora related radical such as chloroallyl, cyclopropyl-methyl or propargyl,and

X is the anion of an acid, especially a chloride, bromide, iodide ormethylsulfate anion.

The compounds are synthesized as described in U.S. Pat. No. 4,176,186,the disclosure of which is incorporated herein by reference. Aparticularly preferred noroxymorphone derivative is methylnaltrexone,but other compounds represented by the above formula are also suitable.

Methylnaltrexone or other noroxymorphone derivatives may be administeredto the patient either enterally or parenterally. However, a preferredmethod of administration is by injection. Nausea and emesis may followafter even a single dose of morphine, unlike intestinal immobility whichis usually the effect of chronic repeated usage of the drug.Consequently, it is contemplated that the patient will be given aninjection of methylnaltrexone prior to surgery or other occasion whenmorphine is used to treat acute pain.

As illustrated by the following Controls and Examples, our studies showthat methylnaltrexone inhibits emesis when administered either togetherwith the morphine or before the morphine is administered. It is thoughtthat methylnaltrexone or other quaternary noroxymorphone derivatives maybe administered up to two hours before the administration of morphine,but that period may be variable. In our studies, methylnaltrexone wasadministered intramuscularly by means of a syringe. It was foundeffective when administered in the same syringe as morphine and alsowhen administered up to 30 minutes before the administration ofmorphine. Methylnaltrexone may also be administered enterally orparenterally by other means. It has been found to be effective in therange of about 0.25 mg/kg to about 1.0 mg/kg.

The effect of methylnaltrexone in reversing the emetic effects ofmorphine is illustrated herein. The unit of mg/kg refers to milligramsof substance administered per kilograms of body weight.

CONTROL 1 AND EXAMPLE 1

One mg/kg of morphine was administered intramuscularly to five dogs.Four dogs vomited. In each instance, vomiting occurred within fourminutes. On a different day the same dose of morphine was administeredintramuscularly to the same five dogs in the same syringe with 1 mg/kgof methylnaltrexone. None of the dogs vomited.

CONTROL 2 AND EXAMPLE 2

Six dogs were given intramuscular doses of 1 mg/kg of morphine. All sixdogs vomited. On an additional day the same dose of morphine wascombined with 0.5 mg/kg of methylnaltrexone and administered in the samesyringe to the same dogs. None of the dogs vomited.

CONTROL 3 AND EXAMPLE 3

One mg/kg of morphine was administered intramuscularly to three dogs.All three dogs vomited. On an additional day the morphine was combinedwith 0.25 mg/kg of methylnaltrexone and administered in the samesyringe. None of the dogs vomited.

CONTROL 4 AND EXAMPLE 4

Methylnaltrexone was administered to two dogs prior to theadministration of 1 mg/kg morphine. In one dog, 0.5 mg/kg ofmethylnaltrexone was administered intramuscularly 15 minutes before themorphine. No vomiting occurred. In the second dog, the same dose ofmethylnaltrexone was administered 30 minutes before the administrationof morphine. No vomiting occurred.

The administration of methylnaltrexone alone was found to produce nonoticeable effects in the animals. Previous studies with larger doses ofmethylnaltrexone have demonstrated that unlike the non-quaternarynaltrexone, methylnaltrexone does not precipitate withdrawal systems inmorphine-tolerant dogs. Russell et al., Eur. J. Pharmacol. 78: 255-261(1982), incorporated herein by reference. Methylnaltrexone has not beenfound to interfere with the analgesic activity of morphine or othernarcotics.

What is claimed is:
 1. A method for preventing or relieving nausea andemesis associated with the use of narcotic analgesics in warm-bloodedanimals, which comprises administering to an animal prone towards nauseaor emesis on receiving narcotic analgesics, an effective amount of atleast one nausea and emesis relieving compound of the formula: ##STR3##wherein R is allyl or a related radical such as chloroallyl,cyclopropyl-methyl or propargyl, andX is the anion of an acid,especially a chloride, bromide, iodide or methylsulfate anion, prior toor simultaneously with administration of the narcotic analgesic.
 2. Amethod as claimed in claim 1, where the compound is administered to theanimal in an amount between about 0.25 mg/kg and about 1.0 mg/kg.
 3. Amethod as claimed in claim 1, where the compound is administered to theanimal enterally.
 4. A method as claimed in claim 1, where the compoundis administered to the animal parenterally.
 5. A method as claimed inclaim 4, where the compound is administered to the animal by injection.6. A method as claimed in claim 1, where the compound is administered tothe animal prior to the administration of the narcotic analgesic.
 7. Amethod as claimed in claim 6, where the compound is administered to theanimal up to about two hours prior to the administration of the narcoticanalgesic.
 8. A method as claimed in claim 1, where the compound isadministered to the animal concurrently with the administration of thenarcotic analgesic.
 9. A method as claimed in claim 1, where thecompound comprises methylnaltrexone.
 10. A method for preventing orrelieving nausea and emesis associated with the use of narcoticanalgesics in warm-blooded animals, which comprises administering to ananimal prone to exhibit nausea or emesis on administration of narcoticanalgesics, methylnaltrexone in the amount of between about 0.25 mg/kgand about 1.0 mg/kg simultaneous with or up to about two hours prior tothe time of administration of the narcotic analgesic.
 11. A method asclaimed in claim 10, where the methylnaltrexone is administered to theanimal parenterally.